Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations.

Chromosomal translocations encode oncogenic fusion proteins that have been proven to be causally involved in tumorigenesis. Our understanding of whether such genomic alterations also affect non-coding RNAs is limited, and their impact on circular RNAs (circRNAs) has not been explored. Here, we show that well-established cancer-associated chromosomal translocations give rise to fusion circRNAs (f-circRNA) that are produced from transcribed exons of distinct genes affected by the translocations. F-circRNAs contribute to cellular transformation, promote cell viability and resistance upon therapy, and have tumor-promoting properties in in vivo models. Our work expands the current knowledge regarding molecular mechanisms involved in cancer onset and progression, with potential diagnostic and therapeutic implications.

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy.

Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis. Surprisingly little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. We report that the transcriptional regulator heat shock factor 1 (HSF1) is frequently activated in cancer-associated fibroblasts (CAFs), where it is a potent enabler of malignancy. HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely structured to support malignancy in a non-cell-autonomous way. Two central stromal signaling molecules-TGF-ß and SDF1-play a critical role. In early-stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. Thus, tumors co-opt the ancient survival functions of HSF1 to orchestrate malignancy in both cell-autonomous and non-cell-autonomous ways, with far-reaching therapeutic implications.

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2.

While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here, we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition.

Artificial Intelligence Enables Quantitative Assessment of Ulcerative Colitis Histology.

Ulcerative colitis is a chronic inflammatory bowel disease that is characterized by a relapsing and remitting course. Assessment of disease activity critically informs treatment decisions. In addition to endoscopic remission, histologic remission is emerging as a treatment target and a key factor in the evaluation of disease activity and therapeutic efficacy. However, manual pathologist evaluation is semiquantitative and limited in granularity. Machine learning approaches are increasingly being developed to aid pathologists in accurate and reproducible scoring of histology, enabling precise quantitation of clinically relevant features. Here, we report the development and validation of convolutional neural network models that quantify histologic features pertinent to ulcerative colitis disease activity, directly from hematoxylin and eosin-stained whole slide images. Tissue and cell model predictions were used to generate quantitative human-interpretable features to fully characterize the histology samples. Tissue and cell predictions showed comparable agreement to pathologist annotations, and the extracted slide-level human-interpretable features demonstrated strong correlations with disease severity and pathologist-assigned Nancy histological index scores. Moreover, using a random forest classifier based on 13 human-interpretable features derived from the tissue and cell models, we were able to accurately predict Nancy histological index scores, with a weighted kappa (κ = 0.91) and Spearman correlation (⍴ = 0.89, P < .001) when compared with pathologist consensus Nancy histological index scores. We were also able to predict histologic remission, based on the absence of neutrophil extravasation, with a high accuracy of 0.97. This work demonstrates the potential of computer vision to enable a standardized and robust assessment of ulcerative colitis histopathology for translational research and improved evaluation of disease activity and prognosis.

SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression.

The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.

A Machine Learning Approach to Liver Histological Evaluation Predicts Clinically Significant Portal Hypertension in NASH Cirrhosis.

BACKGROUND AND AIMS: The hepatic venous pressure gradient (HVPG) is the standard for estimating portal pressure but requires expertise for interpretation. We hypothesized that HVPG could be extrapolated from liver histology using a machine learning (ML) algorithm. APPROACH AND RESULTS: Patients with NASH with compensated cirrhosis from a phase 2b trial were included. HVPG and biopsies from baseline and weeks 48 and 96 were reviewed centrally, and biopsies evaluated with a convolutional neural network (PathAI, Boston, MA). Using trichrome-stained biopsies in the training set (n = 130), an ML model was developed to recognize fibrosis patterns associated with HVPG, and the resultant ML HVPG score was validated in a held-out test set (n = 88). Associations between the ML HVPG score with measured HVPG and liver-related events, and performance of the ML HVPG score for clinically significant portal hypertension (CSPH) (HVPG ≥ 10 mm Hg), were determined. The ML-HVPG score was more strongly correlated with HVPG than hepatic collagen by morphometry (ρ = 0.47 vs. ρ = 0.28; P < 0.001). The ML HVPG score differentiated patients with normal (0-5 mm Hg) and elevated (5.5-9.5 mm Hg) HVPG and CSPH (median: 1.51 vs. 1.93 vs. 2.60; all P < 0.05). The areas under receiver operating characteristic curve (AUROCs) (95% CI) of the ML-HVPG score for CSPH were 0.85 (0.80, 0.90) and 0.76 (0.68, 0.85) in the training and test sets, respectively. Discrimination of the ML-HVPG score for CSPH improved with the addition of a ML parameter for nodularity, Enhanced Liver Fibrosis, platelets, aspartate aminotransferase (AST), and bilirubin (AUROC in test set: 0.85; 95% CI: 0.78, 0.92). Although baseline ML-HVPG score was not prognostic, changes were predictive of clinical events (HR: 2.13; 95% CI: 1.26, 3.59) and associated with hemodynamic response and fibrosis improvement. CONCLUSIONS: An ML model based on trichrome-stained liver biopsy slides can predict CSPH in patients with NASH with cirrhosis.

Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH.

BACKGROUND AND AIMS: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease. APPROACH AND RESULTS: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients. CONCLUSIONS: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.

A Machine Learning Approach Enables Quantitative Measurement of Liver Histology and Disease Monitoring in NASH.

BACKGROUND AND AIMS: Manual histological assessment is currently the accepted standard for diagnosing and monitoring disease progression in NASH, but is limited by variability in interpretation and insensitivity to change. Thus, there is a critical need for improved tools to assess liver pathology in order to risk stratify NASH patients and monitor treatment response. APPROACH AND RESULTS: Here, we describe a machine learning (ML)-based approach to liver histology assessment, which accurately characterizes disease severity and heterogeneity, and sensitively quantifies treatment response in NASH. We use samples from three randomized controlled trials to build and then validate deep convolutional neural networks to measure key histological features in NASH, including steatosis, inflammation, hepatocellular ballooning, and fibrosis. The ML-based predictions showed strong correlations with expert pathologists and were prognostic of progression to cirrhosis and liver-related clinical events. We developed a heterogeneity-sensitive metric of fibrosis response, the Deep Learning Treatment Assessment Liver Fibrosis score, which measured antifibrotic treatment effects that went undetected by manual pathological staging and was concordant with histological disease progression. CONCLUSIONS: Our ML method has shown reproducibility and sensitivity and was prognostic for disease progression, demonstrating the power of ML to advance our understanding of disease heterogeneity in NASH, risk stratify affected patients, and facilitate the development of therapies.

Computational pathology definitions, best practices, and recommendations for regulatory guidance: a white paper from the Digital Pathology Association.

In this white paper, experts from the Digital Pathology Association (DPA) define terminology and concepts in the emerging field of computational pathology, with a focus on its application to histology images analyzed together with their associated patient data to extract information. This review offers a historical perspective and describes the potential clinical benefits from research and applications in this field, as well as significant obstacles to adoption. Best practices for implementing computational pathology workflows are presented. These include infrastructure considerations, acquisition of training data, quality assessments, as well as regulatory, ethical, and cyber-security concerns. Recommendations are provided for regulators, vendors, and computational pathology practitioners in order to facilitate progress in the field. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Molecular mechanisms linking high body mass index to breast cancer etiology in post-menopausal breast tumor and tumor-adjacent tissues.

PURPOSE: In post-menopausal women, high body mass index (BMI) is an established breast cancer risk factor and is associated with worse breast cancer prognosis. We assessed the associations between BMI and gene expression of both breast tumor and adjacent tissue in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) diseases to help elucidate the mechanisms linking obesity with breast cancer biology in 519 post-menopausal women from the Nurses' Health Study (NHS) and NHSII. METHODS: Differential gene expression was analyzed separately in ER+ and ER- disease both comparing overweight (BMI ≥ 25 to < 30) or obese (BMI ≥ 30) women to women with normal BMI (BMI < 25), and per 5 kg/m2 increase in BMI. Analyses controlled for age and year of diagnosis, physical activity, alcohol consumption, and hormone therapy use. Gene set enrichment analyses were performed and validated among a subset of post-menopausal cases in The Cancer Genome Atlas (for tumor) and Polish Breast Cancer Study (for tumor-adjacent). RESULTS: No gene was differentially expressed by BMI (FDR < 0.05). BMI was significantly associated with increased cellular proliferation pathways, particularly in ER+ tumors, and increased inflammation pathways in ER- tumor and ER- tumor-adjacent tissues (FDR < 0.05). High BMI was associated with upregulation of genes involved in epithelial-mesenchymal transition in ER+ tumor-adjacent tissues. CONCLUSIONS: This study provides insights into molecular mechanisms of BMI influencing post-menopausal breast cancer biology. Tumor and tumor-adjacent tissues provide independent information about potential mechanisms.

Inconsistency in large pharmacogenomic studies.

Two large-scale pharmacogenomic studies were published recently in this journal. Genomic data are well correlated between studies; however, the measured drug response data are highly discordant. Although the source of inconsistencies remains uncertain, it has potential implications for using these outcome measures to assess gene-drug associations or select potential anticancer drugs on the basis of their reported results.

Using deep convolutional neural networks to identify and classify tumor-associated stroma in diagnostic breast biopsies.

The breast stromal microenvironment is a pivotal factor in breast cancer development, growth and metastases. Although pathologists often detect morphologic changes in stroma by light microscopy, visual classification of such changes is subjective and non-quantitative, limiting its diagnostic utility. To gain insights into stromal changes associated with breast cancer, we applied automated machine learning techniques to digital images of 2387 hematoxylin and eosin stained tissue sections of benign and malignant image-guided breast biopsies performed to investigate mammographic abnormalities among 882 patients, ages 40-65 years, that were enrolled in the Breast Radiology Evaluation and Study of Tissues (BREAST) Stamp Project. Using deep convolutional neural networks, we trained an algorithm to discriminate between stroma surrounding invasive cancer and stroma from benign biopsies. In test sets (928 whole-slide images from 330 patients), this algorithm could distinguish biopsies diagnosed as invasive cancer from benign biopsies solely based on the stromal characteristics (area under the receiver operator characteristics curve = 0.962). Furthermore, without being trained specifically using ductal carcinoma in situ as an outcome, the algorithm detected tumor-associated stroma in greater amounts and at larger distances from grade 3 versus grade 1 ductal carcinoma in situ. Collectively, these results suggest that algorithms based on deep convolutional neural networks that evaluate only stroma may prove useful to classify breast biopsies and aid in understanding and evaluating the biology of breast lesions.

The molecular basis of breast cancer pathological phenotypes.

The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

EZH2 protein expression in normal breast epithelium and risk of breast cancer: results from the Nurses' Health Studies.

BACKGROUND: Enhancer of zeste homolog 2 (EZH2) is a polycomb-group protein that is involved in stem cell renewal and carcinogenesis. In breast cancer, increased EZH2 expression is associated with aggressiveness and has been suggested to identify normal breast epithelium at increased risk of breast cancer development. However, the association between EZH2 expression in benign breast tissue and breast cancer risk has not previously been evaluated in a large prospective cohort. METHODS: We examined the association between EZH2 protein expression and subsequent breast cancer risk using logistic regression in a nested case-control study of benign breast disease (BBD) and breast cancer within the Nurses' Health Studies. EZH2 immunohistochemical expression in normal breast epithelium and stroma was evaluated by computational image analysis and its association with breast cancer risk was analyzed after adjusting for matching factors between cases and controls, the concomitant BBD diagnosis, and the Ki67 proliferation index. RESULTS: Women with a breast biopsy in which more than 20% of normal epithelial cells expressed EZH2 had a significantly increased risk of developing breast cancer (odds ratio (OR) 2.95, 95% confidence interval (CI) 1.11-7.84) compared to women with less than 10% EZH2 epithelial expression. The risk of developing breast cancer increased for each 5% increase in EZH2 expression (OR 1.22, 95% CI 1.02-1.46, p value 0.026). Additionally, women with high EZH2 expression and low estrogen receptor (ER) expression had a 4-fold higher risk of breast cancer compared to women with low EZH2 and low ER expression (OR 4.02, 95% CI 1.29-12.59). CONCLUSIONS: These results provide further evidence that EZH2 expression in the normal breast epithelium is independently associated with breast cancer risk and might be used to assist in risk stratification for women with benign breast biopsies.

Alcohol consumption and breast tumor gene expression.

BACKGROUND: Alcohol consumption is an established risk factor for breast cancer and the association generally appears stronger among estrogen receptor (ER)-positive tumors. However, the biological mechanisms underlying this association are not completely understood. METHODS: We analyzed messenger RNA (mRNA) microarray data from both invasive breast tumors (N = 602) and tumor-adjacent normal tissues (N = 508) from participants diagnosed with breast cancer in the Nurses' Health Study (NHS) and NHSII. Multivariable linear regression, controlling for other known breast cancer risk factors, was used to identify differentially expressed genes by pre-diagnostic alcohol intake. For pathway analysis, we performed gene set enrichment analysis (GSEA). Differentially expressed genes or enriched pathway-defined gene sets with false discovery rate (FDR) <0.1 identified in tumors were validated in RNA sequencing data of invasive breast tumors (N = 166) from The Cancer Genome Atlas. RESULTS: No individual genes were significantly differentially expressed by alcohol consumption in the NHS/NHSII. However, GSEA identified 33 and 68 pathway-defined gene sets at FDR <0.1 among 471 ER+ and 127 ER- tumors, respectively, all of which were validated. Among ER+ tumors, consuming 10+ grams of alcohol per day (vs. 0) was associated with upregulation in RNA metabolism and transport, cell cycle regulation, and DNA repair, and downregulation in lipid metabolism. Among ER- tumors, in addition to upregulation in RNA processing and cell cycle, alcohol intake was linked to overexpression of genes involved in cytokine signaling, including interferon and transforming growth factor (TGF)-ß signaling pathways, and translation and post-translational modifications. Lower lipid metabolism was observed in both ER+ tumors and ER+ tumor-adjacent normal samples. Most of the significantly enriched gene sets identified in ER- tumors showed a similar enrichment pattern among ER- tumor-adjacent normal tissues. CONCLUSIONS: Our data suggest that moderate alcohol consumption (i.e. 10+ grams/day, equivalent to one or more drinks/day) is associated with several specific and reproducible biological processes and pathways, which adds potential new insight into alcohol-related breast carcinogenesis.

Assessment of Ki67 expression for breast cancer subtype classification and prognosis in the Nurses' Health Study.

PURPOSE: Ki67 is a proliferation marker commonly assessed by immunohistochemistry in breast cancer, and it has been proposed as a clinical marker for subtype classification, prognosis, and prediction of therapeutic response. However, the clinical utility of Ki67 is limited by the lack of consensus on the optimal cut point for each application. METHODS: We assessed Ki67 by immunohistochemistry using Definiens digital image analysis (DIA) in 2653 cases of incident invasive breast cancer diagnosed in the Nurses' Health Study from 1976 to 2006. Ki67 was scored as continuous percentage of positive tumor cells, and dichotomized at various cut points. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models for distant recurrence, breast cancer-specific mortality and overall mortality in relation to luminal subtypes defined with various Ki67 cut points, adjusting for breast cancer prognostic factors, clinico-pathologic features and treatment. RESULTS: DIA was highly correlated with manual scoring of Ki67 (Spearman correlation ρ = 0.86). Mean Ki67 score was higher in grade-defined luminal B (12.6%), HER2-enriched (17.9%) and basal-like (20.6%) subtypes compared to luminal A (8.9%). In multivariable-adjusted models, luminal B tumors had higher breast cancer-specific mortality compared to luminal A cancer classified using various cut points for Ki67 positivity including the 14% cut point routinely reported in the literature (HR 1.38, 95% CI 1.11-1.72, p = 0.004). There was no significant difference in clinical outcomes for ER- tumors according to Ki67 positivity defined at various cut points. CONCLUSIONS: Assessment of Ki67 in breast tumors by DIA was a robust and quantitative method. Results from this large prospective cohort study provide support for the clinical relevance of using Ki67 at the 14% cut point for luminal subtype classification and breast cancer prognosis.

Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes.

PURPOSE: We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy. METHODS: This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case-control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses' Health Study, Nurses' Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size ≥2 cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy. RESULTS: Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non-aggressive tumors (≥51 vs. 11-25% OR 2.50, 95% CI 1.94-3.22 vs. OR 2.03, 95% CI 1.70-2.43, p-heterogeneity = 0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41-0.70 vs. OR 0.71, 95% CI 0.59-0.85, p-heterogeneity = 0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (≥51 vs. 11-25% OR 3.24, 95% CI 1.75-6.00 vs. OR 1.93, 95% CI 1.25-2.98, p-heterogeneity = 0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21-0.85 vs. OR 0.56, 95% CI 0.35-0.89, p-heterogeneity = 0.01), even though the interaction was not significant. CONCLUSION: Our findings suggest that associations of mammographic density with breast cancer risk differ by tumor aggressiveness. While there was no strong evidence that these associations differed by menopausal status or hormone therapy, they did appear more prominent among current estrogen+progesterone users.

Proceedings of the third international molecular pathological epidemiology (MPE) meeting.

Molecular pathological epidemiology (MPE) is a transdisciplinary and relatively new scientific discipline that integrates theory, methods, and resources from epidemiology, pathology, biostatistics, bioinformatics, and computational biology. The underlying objective of MPE research is to better understand the etiology and progression of complex and heterogeneous human diseases with the goal of informing prevention and treatment efforts in population health and clinical medicine. Although MPE research has been commonly applied to investigating breast, lung, and colorectal cancers, its methodology can be used to study most diseases. Recent successes in MPE studies include: (1) the development of new statistical methods to address etiologic heterogeneity; (2) the enhancement of causal inference; (3) the identification of previously unknown exposure-subtype disease associations; and (4) better understanding of the role of lifestyle/behavioral factors on modifying prognosis according to disease subtype. Central challenges to MPE include the relative lack of transdisciplinary experts, educational programs, and forums to discuss issues related to the advancement of the field. To address these challenges, highlight recent successes in the field, and identify new opportunities, a series of MPE meetings have been held at the Dana-Farber Cancer Institute in Boston, MA. Herein, we share the proceedings of the Third International MPE Meeting, held in May 2016 and attended by 150 scientists from 17 countries. Special topics included integration of MPE with immunology and health disparity research. This meeting series will continue to provide an impetus to foster further transdisciplinary integration of divergent scientific fields.